ABSTRACT Vaccination represents the single most effective and cost effective medical intervention devised to date, saving lives and reducing morbidity and disability for billions of humans. Despite the early success of the oral polio vaccine, most vaccines are delivered parenterally, and as such are associated with pain, non-compliance, biohazardous medical waste and strict requirements for expensive production, transport and storage logistics (the ?cold chain?) and for trained technical personnel. Oral/mucosal vaccine strategies eliminate or significantly reduce these drawbacks. The potential use of Arthrospira platensis (commonly called Spirulina) as an oral vaccine delivery platform is highly attractive, given its safety profile, rich nutritional content and wide acceptance as a human food source. At Lumen Bioscience, we utilize a proprietary and patent-pending technique to genetically engineer Spirulina to express heterologous proteins. Lumen Bioscience's Spirulina platform consists of recombinant strains designed to express viral capsid proteins that assemble and form durable high-order complexes commonly called virus-like particles (VLPs). Parenterally-administered VLPs have been used in humans for prevention of infections with human papilloma and hepatitis B viruses and malaria parasites. Orally-administered Spirulina-expressed VLPs have been engineered to efficiently express pathogen-derived antigens inserted into the exterior-facing VLP domains. Here, VLPs bearing epitopes derived from Plasmodium yoelii circumsporozoite protein (CSP) and other antigens were expressed in Spirulina and P. yoelii CSP-VLP-expressing Spirulina were administered orally to mice. This vaccine induced high titer systemic anti-CSP IgG, which conferred in vitro and in vivo protection against sporozoite invasion. This project aims to optimize and develop the oral Spirulina vaccine model as a safe oral pre-erythrocytic malaria vaccine.